Cirrhosis, viral hepatitis, and toxic drug effects can all trigger apoptosis in the liver as a means to remove unwanted cells. The Fas "death receptor" pathway constitutes a major physiological mechanism to achieve this. Liver homeostasis requires that the removal of diseased and damages hepatocytes is accompanied by their coordinated replacement. The arylhydrocarbon receptor (AhR) is a ligand-activated transcription factor known to regulate both apoptotic and proliferative processes. The long-term goal of the investigators is to understand mechanistically how the AhR contributes to tissue homeostasis by regulating cell growth and cell death. They have identified a component critical for AhR function: namely the Retinoblastoma tumor suppressor protein (pRb). The evidence reveals pRb to be a coactivator in AhR-mediated cell cycle control, and in Fas ligand-induced apoptosis. Specifically, they have observed that reintroduction of the AhR into AhR-negative liver cells dramatically increases Fas ligand-induced apoptosis. Their hypothesis is that the AhR plays an important role in liver homeostasis, in part by regulating apoptosis in a process dependent on an AhR-pRb interaction. The goal of this proposal is to characterize the AhR-pRb interaction and to examine the role of AhR in Fas mediated liver apoptosis. Specific Aim 1 will use genetic and pharmacological strategies to examine whether a transcriptionally competent AhR complex is required to modulate the Fas-mediated apoptosis seen in hepatocytes. Specific Aim 2 will characterize the AhR-pRb interaction involving the receptor's glutamine-rich region and examine the functional significance of the interaction. Binding studies will identify the precise amino acids involved in the protein-protein interaction, and their functional importance confirmed by expression studies and cell permeable peptides mimicking the interaction. Specific Aim 3 will examine the role of the AhR in Fas-mediated liver apoptosis in vivo. The event of hepatic apoptosis induced by the Jo2 anti-Fas antibody will be assessed as a function of AhR status and activity.